Fibroblast STAT3 Activation Drives Organ-Specific Premetastatic Niche Formation

Date:	January 2 2026
PMID:	PMC12757723
Category:	N/A
Authors:	Emily L Lasse Opsahl, Carlos E Espinoza, Alberto C Olivei, Jude Ogechukwu Okoye, Hannah Watkoske, Megan T Hoffman, Faith R Avritt, Ahmed M Elhossiny, Allison C Bischoff, Katelyn L Donahue, Mary Poggi, Padma Kadiyala, Nandini Arya, Jiaqi Shi, Kyoung Eun Lee, Yaqing Zhang, Eileen S Carpenter, Julianne M Szczepanski, Timothy L Frankel, Marina Pasca di Magliano
Abstract:

Pancreatic cancer is associated with a high rate of metastasis and poor prognosis. The formation of a premetastatic niche (PMN) facilitates cancer cell spread and contributes to cancer mortality. Using murine pancreatic cancer models based on expression of oncogenic KRAS in the pancreas epithelium, we discovered that remodeling of the lung microenvironment occurred in mice bearing pancreatic precursor lesions prior to cancer formation. This early-lesion PMN resembled the PMN in cancer-bearing mice, and both feature characteristics of overt metastasis, such as transcriptional reprogramming, activation of fibroblast STAT3 signaling, and infiltration of immunosuppressive arginase 1-positive macrophages. Both patients with pancreatic cancer and mouse models demonstrated elevated serum IL6. Inactivating oncogenic KRAS reduced serum IL6 and reverted fibroblast STAT3 phosphorylation in mouse lungs; loss of lung fibroblast STAT3 phosphorylation was similarly observed when mice were treated with the pan-RAS inhibitor RMC-7977. Whereas arginase 1-positive macrophage infiltration was dispensable for fibroblast STAT3 activation, IL6 blockade inhibited lung fibroblast STAT3 activation. Functionally, fibroblast STAT3 activation was necessary for lung metastasis establishment and growth. Interestingly, activation of STAT3 in the PMN was present in the lungs but not in the liver, in which fibroblast reprogramming occurred only in overt metastasis, pointing to organ-specific PMN formation. In human metastasis samples, phosphorylated STAT3 in fibroblasts was similarly more abundant in the lungs than liver. Together, these data point to organ-specific mechanisms driving formation of the PMN and indicate that reprogramming of the microenvironment prior to metastasis might support early dissemination of pancreatic cancer.

Significance: Pancreatic oncogenic KRAS drives premetastatic niche formation in the lungs, but not liver, through fibroblast STAT3 activation to promote metastasis, indicating a lung-specific vulnerability for treating pancreatic cancer metastasis. See related commentary by Mucciolo and Biffi, p. 7.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center